PROJECT SUMMARY Millions of Americans are suffering from the devastation of cognition decline and other neurological dysfunctions due to one of the neurodegenerative diseases of tauopathy. Some of the prominent tauopathies include Alzheimer?s disease, Pick?s disease, traumatic brain injury, and chronic encephalopathy. There is no cure for any of the tauopathies, and the actual cause or exogenous risk factors are unknown. Tauopathies share the common pathological deposition of abnormal, hyperphosphorylated tau protein in selective neurons in the form of neurofibrillary tangles. The normal tau protein is believed to contribute to axonal functions. Hyperphosphorylation causes tau to dissociate from axonal microtubules, and relocates to soma and dendrites where the hyperphosphorylated tau molecules can aggregate into macromolecules of different sizes and morphology. Histologically, the most conspicuous tau aggregates are the neurofibrillary tangles. However, the soluble oligomeric aggregates of hyperphosphorylated tau have been shown in cell and animal models to be cytotoxic, and can even spread from the diseased to healthy neurons in a prion-like fashion. In theory, small-molecule compounds that can inhibit the aggregation of tau are promising drugs for tauopathy treatment. Conversely, those that trigger or enhance aggregation of hyperphosphorylated tau are potential risk factors. Whereas compounds with potential therapeutic values are yet to be discovered, we have evidence that several neurological prescription drugs linked epidemiologically to elevated risks of Alzheimer?s disease can effectively facilitate the in vitro aggregation of hyperphosphorylated tau, but not its unphosphorylated tau counterpart. Dr. Kuo?s team from Michigan State University obtained results suggesting that certain pharmaceutical and environmental risk factors for tauopathies may be identifiable via the test for their ability to trigger the formation of pathogenic aggregates of hyperphosphorylated tau. During Phase I of this STTR, Cayman Chemical will collaborate with Dr. Kuo?s team to develop novel assays that feature the aggregation of different classes of hyperphosphorylated tau. These assays, based on the PIMAX method invented by the Kuo lab, will be then used to screen Cayman benzodiazepine collection of drugs. Pending successful development of the assay platform, our Phase II program will focus on implementing the manufacturing scale-up of the assay kits. This new platform, when available, will impact significantly the sectors of public health and pharmaceutical safety. Successful identification and elimination of tauopathy risk factors will directly benefit a large population of patients and their family members. Better understanding of the devastating tauopathies via studies of these risk factors will also promote the development of effective therapeutic and preventative regimes.